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001-es BibID:BIBFORM082950
Első szerző:Lowe, Patrick
Cím:Inhibition of the Inflammasome Signaling Cascade Reduces Alcohol Consumption in Female But Not Male Mice / Patrick P. Lowe, Yeonhee Cho, David Tornai, Sahin Coban, Donna Catalano, Gyongyi Szabo
Dátum:2020
ISSN:0145-6008 1530-0277
Megjegyzések:BACKGROUND: Alcohol use disorder is a significant societal and medical burden that is associated with both organ pathology and addiction. Excessive alcohol use results in neuroinflammation characterized by activation of the inflammasome, a multiprotein complex, and IL-1? increase in the brain. Recent studies suggest that inflammation could contribute to alcohol addiction. Here, we targeted components of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome cascade, which senses and responds to immunologic stimuli, to determine whether NLRP3 inhibition modulates alcohol consumption. METHODS: C57BL/6J male and female mice were provided a 2-bottle choice of alcohol at increasing concentrations (3, 6, 9, and 12%, 4 days each) or water, and some were treated with daily injections of an NLRP3 inhibitor (MCC950), a caspase-1 inhibitor (VX765), IL-1 receptor antagonist (IL-1ra; anakinra), or vehicle injection. RESULTS: Treatment with VX765, MCC950, and IL-1ra significantly reduced alcohol consumption and preference in female mice (p < 0.05). Treatment with MCC950 and IL-1ra reduced alcohol consumption, while IL-1ra reduced alcohol preference in male mice (p < 0.05). VX765 did not affect alcohol consumption or preference in male mice. CONCLUSIONS: These findings highlight gender differences in alcohol preference and demonstrate that inhibition of different steps in inflammasome signaling can reduce alcohol consumption in females. Inhibition of NLRP3 inflammasome activation and the inflammasome-IL-1? cascade opens novel insights into the development of new therapies to address alcohol use disorder in an era of targeted and precision medicine.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Alcohol
Anakinra
NLRP3
Caspase-1
Interleukin-1 Beta
Megjelenés:Alcoholism, Clinical and Experimental Research. - 44 : 2 (2020), p. 567-578. -
További szerzők:Cho, Yeonhee Tornai Dávid (1989-) (hepatológia, biomarker kutatás) Coban, Sahin Catalano, Donna Szabó Gyöngyi
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2.

001-es BibID:BIBFORM082949
Első szerző:Saha, Banishree
Cím:Biomarkers of Macrophage Activation and Immune Danger Signals Predict Clinical Outcomes in Alcoholic Hepatitis / Banishree Saha, David Tornai, Karen Kodys, Adeyinka Adejumo, Patrick Lowe, Craig McClain, Mack Mitchell, Arthur McCullough, Srinivasan Dasarathy, Aimee Kroll-Desrosiers, Bruce Barton, Svetlana Radaeva, Gyongyi Szabo
Dátum:2019
ISSN:0270-9139
Megjegyzések:Although mortality due to acute alcoholic hepatitis (AH) correlates with Model for End-Stage Liver Disease (MELD) scores, biomarkers are critically needed to manage this disease. Increases in inflammatory markers and macrophage activation are associated with acute AH and could be potential biomarkers of clinical events and/or mortality. We enrolled 89 clinically diagnosed AH patients in four US academic medical centers. Plasma from AH patients had a significant increase in gut microbial translocation indicators (endotoxin, bacterial 16S ribosomal DNA) and host response indicators (soluble cluster of differentiation 14 [sCD14] and lipopolysaccharide binding protein [LBP]) compared to controls. Patient MELD score and Glasgow Alcoholic Hepatitis score (GAHS) correlated with endotoxin levels. AH patients also had a significant increase in high mobility group protein 1 (HMGB1), a sterile danger signal molecule, and osteopontin (OPN), a multifunctional phosphoprotein involved in neutrophil activation, compared to controls. Increased levels of OPN positively correlated with increasing MELD score, GAHS, and LBP levels. Consistent with these results, AH patients had significantly increased circulating levels of macrophage activation (sCD163 and sCD206) markers compared to healthy controls, and sCD163 and sCD206 significantly and positively correlated with OPN, HMGB1, and LBP levels as well as with MELD score and GAHS. These findings indicate a connection between microbial translocation, immune cell activation, and AH severity. Plasma sCD14, OPN, sCD163, and sCD206 levels were significantly higher in nonsurvivors than survivors. In multivariate regression models, we identified sCD14, sCD163, and OPN as independent predictors of 90-day mortality, infection, and organ failure development, respectively. Conclusion: Our study suggests that sCD14, LBP, OPN, sCD163, and sCD206 are biomarkers to indicate severity and predict clinical outcomes in AH.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
osteopontin
sCD206
sCD163
LBP
HMGB1
sCD14
organ failure
infection
Megjelenés:Hepatology. - 70 : 4 (2019), p. 1134-1149. -
További szerzők:Tornai Dávid (1989-) (hepatológia, biomarker kutatás) Kodys, Karen Adejumo, Adeyinka Lowe, Patrick McClain, Craig Mitchell, Mack McCullough, Arthur Dasarathy, Srinivasan Kroll-Desrosiers, Aimee Barton, Bruce Radaeva, Svetlana Szabó Gyöngyi
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Intézményi repozitóriumban (DEA) tárolt változat
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3.

001-es BibID:BIBFORM071775
Első szerző:Satishchandran, Abhishek
Cím:MicroRNA 122, Regulated by GRLH2, Protects Livers of Mice and Patients From Ethanol-Induced Liver Disease / Abhishek Satishchandran, Aditya Ambade, Sitara Rao, Ying-Chao Hsueh, Arvin Iracheta-Vellve, David Tornai, Patrick Lowe, Benedek Gyongyosi, Jia Li, Donna Catalano, Li Zhong, Karen Kodys, Jun Xie, Shashi Bala, Guangping Gao, Gyongyi Szabo
Dátum:2018
ISSN:0016-5085
Megjegyzések:BACKGROUND & AIMS:Chronic, excessive alcohol consumption leads to alcoholic liver disease (ALD) characterized by steatosis, inflammation, and eventually cirrhosis. The hepatocyte specific microRNA 122 (MIR122) regulates hepatocyte differentiation and metabolism. We investigated whether an alcohol-induced decrease in level of MIR122 contributes to development of ALD.METHODS:We obtained liver samples from 12 patients with ALD and cirrhosis and 9 healthy individuals (controls) and analyzed them by histology and immunohistochemistry. C57Bl/6 mice were placed on a Lieber-DeCarli liquid diet, in which they were fed ethanol for 8 weeks, as a model of ALD, or a control diet. These mice were also given injections of CCl4, to increase liver fibrosis, for 8 weeks. On day 28, mice with ethanol-induced liver disease and advanced fibrosis, and controls, were given injections of recombinant adeno-associated virus 8 vector that expressed the primary miR-122 transcript (pri-MIR122, to overexpress MIR122 in hepatocytes) or vector (control). Two weeks before ethanol feeding, some mice were given injections of a vector that expressed an anti-MIR122, to knock down its expression. Serum and liver tissues were collected; hepatocytes and liver mononuclear cells were analyzed by histology, immunoblots, and confocal microscopy. We performed in silico analyses to identify targets of MIR122 and chromatin immunoprecipitation quantitative polymerase chain reaction analyses in Huh-7 cells.RESULTS:Levels of MIR122 were decreased in liver samples from patients with ALD and mice on the Lieber-DeCarli diet, compared with controls. Transgenic expression of MIR122 in hepatocytes of mice with ethanol-induced liver disease and advanced fibrosis significantly reduced serum levels of alanine aminotransferase (ALT) and liver steatosis and fibrosis, compared with mice given injections of the control vector. Ethanol feeding reduced expression of pri-MIR122 by increasing expression of the spliced form of the transcription factor grainyhead like transcription factor 2 (GRHL2) in liver tissues from mice. Levels of GRHL2 also were increased in liver tissues from patients with ALD, compared with controls; increases correlated with decreases in levels of MIR122 in human liver. Mice given injections of the anti-MIR122 before ethanol feeding had increased steatosis, inflammation, and serum levels of alanine aminotransferase compared with mice given a control vector. Levels of hypoxia-inducible factor 1 alpha (HIF1?) mRNA, a target of MIR122, were increased in liver tissues from patients and mice with ALD, compared with controls. Mice with hepatocyte-specific disruption of Hif1? developed less-severe liver injury following administration of ethanol, injection of anti-MIR122, or both.CONCLUSIONS:Levels of MIR122 decrease in livers from patients with ALD and mice with ethanol-induced liver disease, compared with controls. Transcription of MIR122 is inhibited by GRHL2, which is increased in livers of mice and patients with ALD. Expression of an anti-MIR122 worsened the severity of liver damage following ethanol feeding in mice. MIR122 appears to protect the liver from ethanol-induced damage by reducing levels of HIF1?. These processes might be manipulated to reduce the severity of ALD in patients.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
alkoholos májbetegség
Megjelenés:Gastroenterology. - 154 : 1 (2018), p. 238-252. -
További szerzők:Ambade, Aditya Rao, Sitara Hsueh, Ying-Chao Iracheta-Vellve, Arvin Tornai Dávid (1989-) (hepatológia, biomarker kutatás) Lowe, Patrick Gyöngyösi Benedek Li, Jia Catalano, Donna Zhong, Li Kodys, Karen Xie, Jun Bala, Shashi Gao, Guangping Szabó Gyöngyi
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DOI
Intézményi repozitóriumban (DEA) tárolt változat
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